Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
Clemens Schafmayer, James Harrison, Stephan Buch, Christina Lange, Matthias Reichert, Philipp Hofer, Francois Cossais, Juozas Kupcinskas, Witigo Schonfels, Bodo Schniewind, Wolfgang Kruis, Jurgen Tepel, Myrko Zobel, Jonas Rosendahl, Thorsten Jacobi, Andreas Walther-Berends, Michael Schroeder, Ilka Vogel, Petr Sergeev, Hans Boedeker, Holger Hinrichsen, Andreas Volk, Jens-Uwe Erk, Greta Burmeister, Alexander Hendricks, Sebastian Hinz, Sebastian Wolff, Martina Bottner, Andrew Wood, Jessica Tyrrell, Robin Beaumont, Melanie Langheinrich, Torsten Kucharzik, Stefanie Brezina, Ursula Huber-Schonauer, Leonora Pietsch, Laura Noack, Mario Brosch, Alexander Herrmann, Raghavan Thangapandi, Hans Schimming, Sebastian Zeissig, Stefan Palm, Gerd Focke, Anna Andreasson, Peter Schmidt, Juergen Weitz, Michael Krawczak, Henry Volzke, Gernot Leeb, Patrick Michl, Wolfgang Lieb, Robert Grutzmann, Andre Franke, Frank Lammert, Thomas Becker, Limas Kupcinskas, Mauro D'Amato, Thilo Wedel, Christian Datz, Andrea Gsur, Michael Weedon, Jochen Hampe
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10(-10) and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.